Optimal T cell activation requires contemporaneous signals through the T cell receptor and costimulatory molecules. CD28, the prototypical costimulatory molecule, upon interaction with its ligands B7-1 and B7-2, plays a crucial role in initial T cell priming. Sharpe et al., Nat. Rev. Immunol. 2:203-209 (2002). CD28-mediated T cell expansion is opposed by another B7-1,2 counter receptor, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), which attenuates the proliferation of recently activated T cells. Krummel et al., J. Exp. Med. 183:2533-2540 (1996); Leach et al., Science 271:1734-1736 (1996). Temporal regulation of CD28 and CTLA-4 expression maintains a balance between activating and inhibitory signals and ensures the development of an effective immune response, while safeguarding against the development of autoimmunity. Blockade of the inhibitory signals mediated by CTLA-4 has been shown to enhance T cell responses and induce tumor rejection in a number of animal models, and monoclonal antibodies to human CTLA-4 have found modest success in ongoing human clinical trials, including durable complete responses in a small subset of patients with metastatic disease. See, e.g. Korman et al, Adv. Immunol. 90:297-339 (2006).
The identification and characterization of additional CD28 and B7 family members PD-1 (programmed death-1), PD-L1 (programmed death ligand-1 or B7-H1), and PD-L2 (B7-DC) has added further complexity to the process of T-cell activation and peripheral tolerance in humans. Similar to the B7-1,2/CTLA-4 interaction, PD-1 interactions with PD-L1 and PD-L2 downregulate central and peripheral immune responses. Fife et al., Immunol. Rev. 224:166-82 (2008). Accordingly, antibody-based blockade of PD-1, like CTLA-4, is also being explored in human clinical trials for the treatment of cancer. See, e.g., Berger et al. Clin. Cancer Res. 14:3044-3051 (2008). Nevertheless, as with CTLA-4, improved therapies are still needed.
Inducible costimulator (ICOS) is a T-cell-specific surface molecule that is structurally related to CD28 and CTLA-4. Hutloff et al., Nature 397:263-266 (1999); Dong et al., Nature 409:97-101 (2001). Initially, the role of ICOS in immune responses was strongly linked to the production of Th2 cytokines, suggesting that ICOS-expressing T cells might play a role in suppressing immune responses. ICOS-deficient mice demonstrated decreased production of the Th2 cytokine interleukin 10, and IL-10 production by regulatory T cells has been associated with the suppression of effector T cell responses in a cell-extrinsic manner. Yoshinaga et al., Nature 402:827-832 (1999); Kohyama et al., Proc. Natl. Acad. Sci. USA 101:4192-97 (2004). Contrarily, however, more recent data suggested that ICOS-expressing T cells might also be involved in autoimmune responses, and CTLA-4 blockade in bladder cancer patients was shown to increase ICOS expression on CD4+ T cells, which cells then produced IFN-gamma and recognized tumor antigen. Yu et al. Nature 450:299-303 (2007); Liakou et al., Proc. Natl. Acad. Sci. USA 105:14987-992 (2008). Further, ICOS has also been shown to be associated with increased survival of both effector memory and regulatory T cells, demonstrating that its functional relevance may not be restricted to regulatory T cells. Burmeister et al., J. Immunol. 180:774-782 (2008). As such, the physiological role of ICOS signaling in the T cell activation process is still being unraveled. Due to this continuing uncertainty, the potential impact of modulating ICOS signaling in the context of cancer therapy is currently unknown.